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Red blood cell (RBC) alloimmunisation with anti-D and anti-K comprise the majority of cases of fetal haemolytic disease requiring intrauterine red cell transfusion (IUT). Few studies have investigated which haematological parameters can predict adverse fetal or neonatal outcomes. The aim of the present study was to identify predictors of adverse outcome, including preterm birth, intrauterine fetal demise (IUFD), neonatal death (NND) and/or neonatal transfusion. We reviewed the records of all pregnancies alloimmunised with anti-K and anti-D, requiring IUT over 27 years at a quaternary fetal centre. We reviewed data for 128 pregnancies in 116 women undergoing 425 IUTs. The median gestational age (GA) at first IUT was significantly earlier for anti-K than for anti-D (24·3 vs. 28·7 weeks, P = 0·004). Women with anti-K required more IUTs than women with anti-D (3·84 vs. 3·12 mean IUTs, P = 0·036) and the fetal haemoglobin (Hb) at first IUT was significantly lower (51.0 vs. 70.5 g/l, P = 0·001). The mean estimated daily decrease in Hb did not differ between the two groups. A greater number of IUTs and a slower daily decrease in Hb (g/l/day) between first and second IUTs were predictive of a longer period in utero. Earlier GA at first IUT and a shorter interval from the first IUT until delivery predicted IUFD/NND. Earlier GA and lower Hb at first IUT significantly predicted need for phototherapy and/or blood product use in the neonate. In the anti-K group, a greater number of IUTs was required in women with a higher titre. Furthermore, the higher the titre, the earlier the GA at which an IUT was required in both groups. The rate of fall in fetal Hb between IUTs decreased, as the number of transfusions increased. Our present study identified pregnancies at considerable risk of an unfavourable outcome with anti-D and anti-K RBC alloimmunisation. Identifying such patients can guide pregnancy management, facilitates patient counselling, and can optimise resource use. Prospective studies can also incorporate these characteristics, in addition to laboratory markers, to further identify and improve the outcomes of these pregnancies., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Early intrauterine transfusion (IUT) is associated with a higher risk of fetal loss. Our objective was to evaluate the efficiciency of intravenous immunoglobulins (IVIG) to postpone the gestational age at first IUT beyond 20 weeks of gestation (WG) compared to the previous pregnancy in case of very severe red blood cell (RBC) alloimmunization., Study Design and Methods: Very severe RBC alloimmunization was defined by a high titer of antibodies and a previous pregnancy complicated by a first IUT before 24 WG and/or perinatal death directly related to alloimmunization. We performed a single-center case-control study. Cases and controls were patients respectively treated with weekly IVIG infusions started before 13 WG, and without., Results: Twenty cases and 21 controls were included. Gestational age (GA) at first IUT was postponed after 20 WG in 18/20 (90 %) of patients treated with IVIG and in 15/21 (71 %) in the control group (p = 0.24). Compared to the previous pregnancy, the GA at first IUT was postponed by a median of 22 [+11; +49] days in the IVIG group and occurred in average 2 days earlier [-17 ; +12] in the non-treated group (p = 0.02). There was no difference between number of IUT and need for exchange-transfusion. IVIG treatment was associated with a significant decrease of antibodies' quantitation., Conclusion: In our series, IVIG tends to differ first IUT beyond 20 WG and have a significant effect in postponing the gestational age of the first IUT in patients with very severe RBC alloimmunization., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Intrauterine transfusion is one of the mainstays of treatment in isoimmunised pregnancies guided by the changes in middle cerebral artery Doppler of the fetus. The common postnatal complications associated with Rh isoimmunisation are high unconjugated bilirubin requiring blood exchange transfusions, cholestasis due to bile inspissation, thrombocytopenia and anaemia. Hyperferritinaemia is an uncommon adverse effect observed in Rh isoimmunised pregnancies. In this case report, we describe the clinical course of a Rh isoimmunised neonate with hyperferritinaemia and transfusion acquired cytomegalovirus disease which resolved. Iron chelation therapy was not necessary., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To evaluate whether Doppler measurement of middle cerebral artery peak systolic velocity (MCA-PSV) for timing subsequent intrauterine transfusions (IUTs) in fetuses that had undergone one IUT for anemia secondary to red-cell alloimmunization is non-inferior to timing based on expected decrease in fetal hematocrit (Hct) or fetal hemoglobin level, without compromising infant hemoglobin at birth., Methods: This was an international, pragmatic multicenter randomized controlled trial. Women with a pregnancy complicated by fetal anemia secondary to red-cell alloimmunization (due to any antibody alone or in combination), as indicated by the need to undergo a single IUT, were eligible for inclusion. Women were randomized to the determination of timing of further transfusion(s) by Doppler measurement of MCA-PSV (MCA-PSV Group), with a serial upward trend of values >1.5 multiples of the median considered indicative of the need for another IUT, or timing of transfusion by a decrease in fetal Hct (fetal Hct Group), with subsequent IUTs timed according to an estimated fall in fetal Hct of 1% per day or fetal hemoglobin of 0.3 g/dL per day, to maintain fetal hemoglobin level between 7 and 10 g/dL. The primary outcome was infant hemoglobin level measured at birth., Results: A total of 71 women were randomized, 36 to the MCA-PSV Group and 35 to the fetal Hct Group. Median gestational age at randomization was 30.3 weeks, the majority of women were Caucasian and non-smokers, 9.9% of women had Kell alloimmunization, and 14% of fetuses were hydropic at their first IUT. No statistically significant differences between the two treatment groups were observed with regard to mean hemoglobin levels at birth (MCA-PSV Group, 10.36 ± 3.82 g/dL vs fetal Hct Group, 12.03 ± 3.14 g/dL; adjusted mean difference -1.56 g/dL (95% CI, -3.24 to 0.13 g/dL); P = 0.070), or the number of IUTs performed after randomization (MCA-PSV Group, 1.75 ± 1.79 vs fetal Hct Group 1.80 ± 1.32; adjusted relative risk 0.88 (95% CI, 0.61-1.26); P = 0.474). There was no statistically significant difference between the two groups with respect to the risk of adverse infant outcomes related to alloimmunization or procedure-related complications., Conclusion: Both Doppler measurement of MCA-PSV and estimation of the decrease in fetal Hct or hemoglobin can be used to determine the timing of second and subsequent IUTs in fetuses with red-cell alloimmunization. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: To evaluate intestinal blood flow changes after intravenous immunoglobulin (IVIg) infusion among neonates with Rh isoimmunization and alloimmune thrombocytopenia., Methods: This prospective observational study was conducted in level III NICU from July 2011 through August 2012. Thirty three consecutive instances (30 neonates) of IVIg treatment (1 g/kg) were studied. Celiac (CA) and superior mesenteric artery (SMA) doppler evaluations were performed immediately prior (baseline), immediately after and 12 to18 h following IVIg infusion. Peak systolic velocity, end diastolic velocity, time-averaged mean velocity, pulsatility index, resistive index and systolic/diastolic ratio were measured. The doppler indices measured immediately after and 12 to 18 h after IVIg infusion were compared with the baseline values., Results: The mean gestation and birth weight of the cohort were 36 ± 2 wk and 2597 ± 563 g respectively. Doppler flow variables measured immediately after and 12 to 18 h after IVIg were comparable to baseline values, in both the arteries. However, systolic/diastolic ratio in SMA immediately post-IVIg was lower than baseline, [median (IQR): 5 (3, 9) vs. 7 (4, 14), respectively; p=0.02]. None of the study infants developed feed intolerance or necrotizing enterocolitis (NEC)., Conclusions: There was no significant change in the celiac and SMA blood flows following IVIg therapy in neonates with Rh isoimmunization and alloimmune thrombocytopenia.

Objectives: Intrauterine transfusion imposes a considerable burden on the fetal circulation by increasing volume and pressure, and a fluid shift from the fetal circulation occurs even during the procedure. The aim of this study was to quantify the intraprocedural fluid shift and to investigate the effect of procedural and fetal characteristics on this fluid shift., Methods: In 95 alloimmunized pregnancies, we calculated fluid shift at the first intrauterine transfusion by determining initial and final blood volumes. We evaluated the association of the fluid shift with the speed and volume of the transfusion, the severity of anemia and the presence of hydrops., Results: Of the included fetuses, 11 were mildly hydropic and four were severely hydropic. A mean fluid shift of 36% of the transfused volume was found. Fluid shift related positively to transfused volume (P < 0.001). The percentage fluid shift of transfused volume was inversely related to the speed of transfusion (mL/kg/min) (P < 0.041) and was not related to the severity of anemia (P = 0.55) or to hydrops (P = 0.66). It was found that younger fetuses had been unintentionally subject to high volumes and speeds of transfusion relative to their size., Conclusions: Around one-third of the transfused volume is lost from the intravascular compartment during the procedure of intrauterine transfusion. There is a large variation between fetuses, partly explained by the volume and speed of the transfusion. Neither severity of anemia nor hydrops plays a clear-cut role, and thus other factors may explain the variation in fluid shift. The probability that hematocrit will still increase after transfusion, as a result of a continuing fluid shift, should be considered in transfusion policy. Advice is given on gestational age-adjusted speed of transfusion., (Copyright © 2012 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To estimate the long-term effects of anemia on the fetal heart by echocardiography of children who received intrauterine blood transfusions for red cell isoimmunization., Methods: Surviving children who received intrauterine transfusions during the period from 1992 to 2003 were identified. Children matched for age and sex were chosen for the control group to create a 1:1 case-control study design. A clinical interview, physical examination, and echocardiography assessment (corrected for body surface area) were performed., Results: Twenty-five children were recruited for the case group and matched to 25 healthy children for the control group. Children in the case group had received a median of four intrauterine transfusion procedures (range 1-7), with a median gestation at initial intrauterine transfusion of 28 weeks (range 22-34 weeks). Hydrops was present in 32%. Median initial hemoglobin was 76 g/L (range 25-133 g/L). Median gestation at delivery was 36 weeks (range 29-38 weeks). The median age of children in the case group was 10.1 years (range 3.6-15.8 years) and of those in the control group was 10.5 years (range 3.8-16.4 years; P=.122). There was no difference in body surface area, baseline heart rate, systolic blood pressure, or diastolic blood pressure between children in the case group and those in the control group. Echocardiography demonstrated three main differences: children in the case group had 9% less left atrial area (95% confidence interval [CI] 2-16% less; P=.02), 10% less ventricular mass (95% CI 1-19% less; P=.039), and an average 11 ms less mitral valve atrial duration (95% CI 3-19 ms less; P=.009) than did those in the control group. These results did not alter when adjusted for isoimmunization severity., Conclusion: Fetal anemia secondary to red cell isoimmunization is associated with a reduction in left ventricular mass and left atrial area in childhood, although resting ventricular function is maintained. We speculate this may be secondary to the prenatal effects of anemia on cardiomyocyte proliferation and differentiation., Level of Evidence: III.

Summary: Rh isoimmunization manifesting as isolated early onset neonatal anemia has not been reported. We describe the presentation of 3 infants who manifested with isolated early severe anemia. All the infants presented early (3 to 7 d of age) with severe pallor. None had clinically significant jaundice. Evidence for hemolysis was present in all and their direct antiglobulin test was positive. To reduce the hemolysis, immunoglobulin was administered after which their hemoglobin improved. This report highlights the possibility of early onset anemia without significant jaundice as the sole manifestation of Rh isoimmunization and the possible beneficial role of immunoglobulin in them.

The purpose of this article is to create the first complete review concerning the role of calprotectin, a calcium- and zinc-binding protein of the S100/calgranulins family, in obstetrics and gynecology. A Medline search was conducted between 6 and 8 June 2009 using the term calprotectin and its synonyms combined with the following ones: calprotectin, obstetrics and gynecology, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, menstrual cycle, pregnancy, fetal implantation, labor, intra-amniotic inflammation, preeclampsia, HELLP syndrome, Rh(-) incompatibility. We found 46 studies which referred to obstetrics and gynecology. We excluded 11 studies which referred to obstetrics and gynecology but did not include enough information about calprotectin, and another two which referred to calprotectin but were not related to subjects of obstetrics and gynecology. Thus, we ended up with 33 studies which contained sufficient information to extract data for this review. All the articles were written in English. It was found that calprotectin is associated with many physiologic and pathologic processes in obstetrics and gynecology, such as: breast cancer, ovarian cancer, endometrial cancer, cervical cancer, cervical and vaginal physiology, menstrual cycle, pregnancy and labor. The role of calprotectin in these conditions is significant. In conclusion, the role of calprotectin seems to be important in several issues of obstetrics and gynecology. For example, calprotectin could be used as a diagnostic, prognostic or metastatic marker in several types of cancer, as a marker of inflammation and as a pharmaceutical target in many conditions. Further studies must be conducted to elucidate this role., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Maternal antibody-mediated fetal red blood cell destruction secondary to non-D Rhesus (Rh) antibodies is a significant cause of hemolytic disease of the newborn (HDN). Here, we report a rare case of severe HDN associated with maternal antibody to Rh e. In addition to severe anemia, the infant developed thrombocytopenia, conjugated hyperbilirubinemia and cholelithiasis. Resolution of the infant's cholelithiasis occurred following treatment with ursodeoxycholic acid.

Objective: To describe the management of five women with severe, early-onset Rh isoimmunization with a series of intraperitoneal transfusions., Methods: Intraperitoneal transfusions were started at 15 to 16 weeks of pregnancy, with small volumes of blood given weekly until the umbilical cord could be successfully entered and further transfusions given intravascularly., Results: The initial range of anti-D immune globulin levels was 24-244 international units, and all women had severe Rh isoimmunization complicating previous pregnancies. No fetus was severely anemic at the first intravascular transfusion (lowest hemoglobin 8.9 g/dL), and there were no fetal losses. Middle cerebral artery peak systolic velocity responded to treatment with intraperitoneal transfusions, suggesting that even at 15 to 16 weeks of gestation it correlates with fetal hemoglobin., Conclusion: This series shows that intraperitoneal transfusions can be used to successfully treat severe, early-onset Rhesus disease.

Objective: This study was undertaken to determine the detection of fetal anemia and false-positive rates by fetal middle cerebral artery peak systolic velocity (MCA-PSV) and the estimated daily decrease of hemoglobin (Hb) in red blood cell alloimmunized pregnancies that had previous fetal transfusions., Study Design: We examined the relation between MCA-PSV measured before cordocentesis, and fetal Hb at the time of the second (n = 42) and third (n = 31) intrauterine blood transfusions. In addition, the daily Hb drop between the transfusions was calculated., Results: The MCA-PSV provided significant prediction of severe anemia (Hb deficit > or = 6 g/dL) for the second but not for the third transfusion. Detection of 95% of severely anemic fetuses was achieved with a false-positive rate of 37% for the second transfusion and 90% for the third, compared with 14% in our previous study for the first transfusion. In patients who had received 2 previous transfusions, the only significant predictor of fetal anemia was the estimation of the Hb from the measured posttransfusion Hb after the second transfusion and the assumption that the rate of decrease in fetal Hb is 0.3 g/dL per day., Conclusion: Prediction of severe fetal anemia after one transfusion is less accurate than in nontransfused fetuses. The MCA-PSV is not useful in predicting severe anemia in fetuses that already had 2 previous transfusions.

Objective: Ductus venosus and inferior vena cava flow velocity was assessed in fetuses in isoimmunized pregnancies., Methods: Examination of 61 fetuses aged 27 to 35 weeks from Rh-erythrocyte antigen isoimmunized women was carried out from June 1999 to June 2004. All fetuses were submitted to the examination of ductus venosus and inferior vena cava flow velocity. Blood samples were collected to determine hemoglobin values and hemoglobin concentration deficits. Accordingly, fetuses were grouped as follows: non-anemic; mildly anemic; moderately anemic and severely anemic fetuses. Comparison of the variation of average flow velocity in the inferior vena cava and ductus venosus across the four groups was carried out using the chi-square test., Results: Inferior vena cava flow velocity was found to be altered in 3.8% of non-anemic fetuses; in 3.1% of the mildly anemic, in 40.0% of those moderately anemic; and in 76.0% of the severely anemic ones. Alteration in ductus venosus flow velocity, in turn, was identified in 7.7% of non-anemic fetuses; 3.1% of mildly anemic; 32.5% of moderately anemic and 68.0% of those severely anemic. Results were statistically significant with p < 0.001., Conclusion: The study shows that alteration of flow velocity in the inferior vena cava and ductus venosus increased with the severity of anemia.

The hemolytic disease of the newborn, originating as a result of sensitization of the mother to the Rh-antigen of erythrocytes of the fetus (Rh-HDN) is one of the most important causes of the loss of a fetus and newborn. One of the pathogenetic mechanisms of Rh-HDN is the hyperbilirubinemia at the expense of the toxiferous fraction of a bilirubin negatively influencing many organs of the child, including the liver. The purpose of the work was the complex study of indexes of a functional condition of a liver newborn with a various degree of gravity Rh-HDN and definition of effectiveness of the conducted therapy. The direct association between severity of illness and indexes of pigmental, excretion and detoxication of the function of the liver in newborns with Rh-HDN has been found. There were found significant relations of ALT/AP, AST/AP, GT/AP, albumin and globulin factors with the degree of cholestasis and toxic damage of the liver. The lack of normalization of indexes of the peptide uptake and the excretion function of the liver on the background of treatment indicate to the necessity of further monitoring of functional condition of the liver and realization of the correction of therapy after discharge of children from the hospital, especially with the serious form of Rh- HDN.

Objective: The middle cerebral artery peak systolic velocity (MCA-PSV) has been successfully used for timing the first 2 transfusions in fetuses at risk for anemia because of maternal red cell alloimmunization. The objective of this study was to assess whether the correlation between the MCA-PSV and fetal hemoglobin is maintained in fetuses that had undergone 2 previous intrauterine transfusions., Study Design: Doppler measurement of MCA-PSV was performed before cordocentesis in 39 fetuses. The timing of the third transfusion was based on traditional criteria. The values of MCA-PSV and hemoglobin were expressed as multiples of the median (MoM). Anemia was defined as mild (hemoglobin <0.84 MoM for a given gestational age, moderate (hemoglobin <0.65 MoM), and severe (hemoglobin <0.55 MoM). Regression analysis was used to assess the correlation between the MCA-PSV MoM and fetal hemoglobin MoM., Results: Gestational age at Doppler study ranged from 22 to 35 weeks. Six fetuses (15%) had normal hemoglobin concentration; 21 (53%) had mild anemia; 7 (20%) had moderate anemia; and 5 (12%) had severe anemia. There was a linear correlation between fetal hemoglobin (y) and the MCA-PSV (x): y = 1.185 - 0.341x., Conclusion: Previously, concerns have been expressed about the accuracy of Doppler prediction of anemia after previous transfusions. Our data suggest that there is a good correlation between the MCA-PSV and fetal hemoglobin in fetuses that have undergone 2 previous transfusions. Our findings expand the clinical situation in which Doppler can be used to monitor red cell alloimmunized pregnancies.

Objectives: To compare different normal reference ranges of fetal blood flow velocity in the middle cerebral artery for predicting fetal anemia., Methods: Eight reference ranges of either middle cerebral artery peak or time-averaged mean velocities were compared using the area under the receiver-operating characteristics (ROC) curve for 113 fetal blood samples from 60 women at risk of fetal red blood cell alloimmunization., Results: The areas under the ROC curves of the different ranges were not significantly different but there were marked differences in sensitivity (range, 7.14-91.78%) and specificity (range, 31.25-96.88%) with the currently used cut-offs. Except for Mari's range, the best theoretical cut-offs, defined as those having the best sensitivity with the best specificity, differed from those in current use, especially when using time-averaged mean velocity., Conclusions: Any of the previously reported reference ranges perform well in the non-invasive prediction of fetal anemia. However, with the exception of Mari's curve, the currently employed cut-offs for predicting fetal anemia should be changed, some of them markedly, in order to provide reliable support for clinical decisions., (Copyright 2005 ISUOG)

Objective: The purpose of this study was to determine the clinical outcome of isoimmunized pregnancies managed primarily by middle cerebral artery peak systolic velocity., Study Design: A retrospective chart review was conducted of isoimmunized pregnancies that underwent ultrasound examinations from January 1, 2001, through May 1, 2003. Ultrasound reports, laboratory tests, and maternal and neonatal charts were reviewed., Results: Women with a clinically significant red blood cell antibody and titer value were included. The study population consisted of 39 women (40 pregnancies, 42 fetuses). Patients with a middle cerebral artery peak systolic velocity of > or =1.5 MoM were offered amniocentesis. Seven pregnancies had an abnormal middle cerebral artery peak systolic velocity. Three of these infants had significant anemia. Six of the 7 pregnancies required an exchange transfusion. None of the 33 pregnancies (35 neonates) with normal middle cerebral artery peak systolic velocity measurements resulted in a neonate with significant anemia or severe hyperbilirubinemia., Conclusion: The clinical outcome of these pregnancies supports the use of middle cerebral artery peak systolic velocity measurements in the management of isoimmunized pregnancies.

Isoimmunization to the Rh(D) antigen and to other red cell antigens remains a potentially severe complication of pregnancy. Although management of this complication is performed best by perinatologists, nurses often are the ones who provide further explanations, answer questions, and assist patients who are trying to understand complex physiology and management plans. Nurses should understand current controversies related to isoimmunization and function as patient advocates if needed. To meet these demands, nurses must continue to refresh their knowledge of isoimmunization and its potential complications and review ever-changing management regimens.

Objectives: To study the correlation of peak systolic velocity in the middle cerebral artery with hemoglobin concentration in fetuses at risk of anemia due to Rhesus isoimmunization., Design: Peak systolic velocity of middle cerebral artery (MCA-PSV) was measured before 66 cordocentesis procedures in 20 isoimmunized fetuses. Reference values were derived from a study of 300 control fetuses. MCA-PSV values and hemoglobin concentrations were expressed as multiples of the median (MoM) for gestational age. The following hemoglobin concentration MoM thresholds defined degrees of anemia: mild, between 0.83 and 0.65; moderate, between 0.64 and 0.55; and severe, less than 0.55. Regression analysis was performed and receiver-operator-characteristic curves were constructed to determine the diagnostic accuracy of different thresholds of MCA-PSV for the prediction of moderate to severe anemia, either at the initial or repeat cordocentesis procedures., Results: The mean (+/-SD) gestational age at cordocentesis was 28.5+/-4.6 weeks. Moderate to severe anemia was observed on 29 (44%) and hydrops on 27 (41%) occasions. MCA-PSV correlated weakly with hemoglobin concentrations. At threshold values 1.50 MoM, the sensitivity, specificity, and negative predictive value for moderate to severe anemia were 9.0, 100, and 48.0% at the initial cordocentesis procedures, and 44.0, 96.0, and 73.0% at repeat cordocentesis procedures, respectively., Conclusions: Although MCA-PSV is highly specific, negative values do not rule out fetal anemia. Further research is required before it can be recommended in clinical practice.

Objective: To evaluate the utilisation measurements of peak systolic velocities in the middle cerebral artery combined with B-mode ultrasound imaging to predict anaemia in an unselected population of pregnancies complicated by alloimmune antibodies known to cause immunological hydrops., Design: Prospective study on an intention-to-treat basis., Setting: Multicentre study in five large tertiary referral centres., Population: One hundred twenty-five fetuses with maternal alloantibodies known to cause immunological hydrops., Methods: If peak systolic velocity and B-mode scan were reassuring the pregnancy was monitored at 7-14 days interval. If either method showed signs of anaemia, an umbilical fetal blood sampling was performed. When the gestational age was greater than 35 weeks, labour was induced., Main Outcome Measure: Moderate to severe anaemia at delivery., Results: Overall sensitivity to detect moderate to severe anaemia below 35 weeks (haemoglobin level below 0.65 multiples of median) was 88%. Specificity was 87%; positive predictive value was 53% and negative predictive value was 98%. The diagnosis of severe anaemia was missed in one fetus; however, the final outcome was good. The method was not useful after 35 weeks., Conclusions: Middle cerebral artery peak systolic velocity is a highly sensitive non-invasive means for determining the degree of anaemia present in red blood cell alloimmunised pregnancies. The widespread use of the Doppler method will minimise fetal complications associated with amniocentesis and fetal blood sampling. Non-invasive measurement of middle cerebral artery peak systolic velocities is more convenient and acceptable to alloimmunised pregnancies and may significantly lower health care costs. A Doppler interval of seven days is recommended.

Aim: To evaluate the detection rate of fetal anemia and pregnancy outcome as related to our policy of monitoring pregnancies with red blood cell alloimmunization., Methods: From August 1997 to July 2000 35 pregnant women with maternal red blood cell alloantibodies were monitored by ultrasonographic measurements of the fetal spleen perimeter and peak systolic Doppler flow velocities of the middle cerebral artery, by semiquantification of maternal antibody titers and by general ultrasonographic and clinical evaluation. According to previous obstetric outcome they all had mild to moderate risk of developing fetal anemia., Results: Eleven fetuses were anemic defined as a hemoglobin value < or = 2SD according to gestational age. A spleen perimeter > + 2SD and a middle cerebral artery peak systolic velocity > 95% prediction interval showed sensitivity and specificity of 64 and 92% and 45 and 100%, respectively. The area under receiver operating characteristic curves was 0.926 (95% CI 0.842-1.000; P < 0.001) for the spleen perimeter and 0.837 (95% CI 0.688-0.987; P < 0.01) for the middle cerebral artery peak systolic velocity. Cordocentesis was performed in one pregnancy only. None of the fetuses developed hydrops and all infants survived. Twelve women delivered before 37 weeks gestation. In 10 patients cesarean section was performed due to possible fetal anemia. Six of the 10 neonates had normal hemoglobin values., Conclusions: The ultrasonographic parameters did not predict all cases of fetal anemia defined as a hemoglobin concentration < or = 2SD according to gestational age. The present policy of monitoring seemed to reduce the number of invasive tests but possibly increased the number of preterm and cesarean deliveries.

Rh isoimmunization is a potentially preventable condition that occasionally is associated with significant perinatal morbidity or mortality. Disease severity may be assessed using the modalities described above and frequently, invasive techniques are required to determine the risk of severe disease. Doppler flow studies appear to offer accurate, noninvasive means of evaluating fetal risk, which may allow for a decrease in invasive diagnostic procedures. The Rh isoimmunized patient, managed by an experienced team, can anticipate a favorable pregnancy outcome.

Anti-D prophylaxis is currently applied in France after birth of an RhD positive infant, after interruption of pregnancy and after some antenatal immunizing events (amniocentesis...). However this program does not cover all the prenatal exposures to fetal RhD antigen, and maternal Rh immunization continues to occur. DNA RhD genotyping of the fetus is now reliably performed on amniotic fluid, and pre diagnostic studies on fetal DNA extracted from maternal plasma are promising. The widespread use of fetal RhD genotyping on maternal blood would allow the antenatal administration of Rh immunoglobuline in all Rh negative patients bearing an Rh positive fetus, insofar as it would preclude exposing the other Rh negative patients to the above plasma derived and rather expensive blood product.

In spite of the progress made since 1970 in specific prevention by anti-rhesus immunoglobulins, and improved management of at-risk pregnancies, allo-immunization due to the erythrocytic Rh 1 antigen (formerly known as Rhesus D or Rh D) remains widespread. In fact, anti-Rh 1 antibodies currently constitute over one-third of the immune antibodies detected after pregnancy. The prevention of allo-immunization against the Rh 1 antigen is therefore still problematical, and concerns approximately one pregnant woman in seven. The etiology and pathology of fetal hemolytic disease have been recalled, and the treatment approach during pregnancy and delivery has been carefully examined. Tests for quantifying the risk of fetomaternal hemorrhage have also been described. This approach aims at improving the methods of preventing allo-immunization (e.g., during pregnancy and delivery) and the efficacy of treatment. It is also stated that if the necessary preventive action is not taken in cases of allo-immunization due to to the Rh 1 antigen, this should be considered a grave medical fault.

Objective: To measure insulin and glucagon concentrations in amniotic fluid (AF) collected near term in basal conditions and after an arginine test in diabetic, rhesus-isoimmunized, and control pregnant women., Methods: At baseline, AF was collected from 44 diabetic, 32 rhesus-isoimmunized, and 27 control pregnant women in late pregnancy. Fifty-two diabetic, six rhesus-isoimmunized, and nine control pregnant women had amniocentesis 2 hours after arginine infusion (30 g intravenous/30 minutes) at 33-36 weeks., Results: Baseline AF glucose concentrations were significantly greater in diabetic women than the other conditions, and they related to the gestational age in the women with hemolytic disease of the newborn. Insulin and glucagon AF content of isoimmunized pregnancies overlapped controls, whereas insulin and insulin/glucagon molar ratios were significantly higher, and glucagon values lower, in diabetic pregnancies compared with isoimmunized and control pregnancies. In isoimmunized pregnancies, the AF concentrations of glucose, insulin, and glucagon were correlated with gestational age (less than 34, 34 weeks or more). The samples collected after arginine infusion, compared with those collected at baseline, showed significantly greater insulin and insulin/glucagon molar ratio values in diabetic (28 +/- 5 versus 11 +/- 1 microU/mL, P = .001; 29.4 +/- 1.7 versus 12.0 +/- 2.8, P = .001) and in Rh pregnant women (18 +/- 6 versus 7.7 +/- 0.7 microU/mL, P = .001; 30 +/- 9 versus 3.4 +/- 0.4 I/G, P = .001), whereas no significant difference was observed in the controls., Conclusion: Basal islet hormone concentrations in AF are modified by maternal diabetes and further influenced by arginine administration. Arginine produces an AF response that is similar in pregnancies complicated by diabetes mellitus and rhesus-isoimmunization, despite different (hyperglycemia and euglycemia) maternal blood glucose levels.

Our purpose was to evaluate the impact of non-invasive assessment of fetal anemia and anti-D antibody quantification on the timing and frequency of invasive procedures in pregnancies complicated by rhesus alloimmunization. Nineteen consecutive non-hydropic pregnancies referred to the fetal medicine center were assigned a prior risk category (none/mild, moderate or severe) and monitored by: (1) serial fetal measurements of umbilical vein maximal flow velocity (UVVmax), liver length and spleen perimeter measurements; and (2) serial anti-D antibody concentration. Invasive tests for fetal anemia (amniocentesis or fetal blood sampling) were deferred in the absence of abnormal ultrasound findings and/or rising antibody levels. In six cases serial non-invasive tests were normal with stable antibody levels, and no invasive tests were performed; four infants were mildly affected, one was unaffected and one required postnatal exchange transfusion. In the remaining 13 affected cases, amniocentesis was performed in nine cases for: elevated UVVmax alone (n = 3), elevated UVVmax and an increased antibody level (n = 2), or normal UVVmax with an increased antibody level (> 15 IU/ml) and severe prior risk category (n = 4). Six fetuses underwent fetal blood sampling (initial hematocrit 9-29%), and five of these had an elevated UVVmax. Liver length and spleen perimeter measurements were increased in only one anemic fetus (hematocrit 13%). Of 17 infants born alive, an elevated UVVmax prior to delivery was predictive of the need for exchange transfusion (six of seven cases with an elevated UVVmax vs. one of ten with a normal UVVmax; chi 2 = 5.73, p = 0.017 with Yates' correction). These preliminary data suggest that pregnancies with a mild or no history of fetal anemia may be monitored by a combination of serial antibody quantification and Doppler monitoring of UVVmax.

Objective: To correlate the peak velocity in the fetal descending aorta, as measured by pulsed Doppler ultrasound, with fetal hematocrit values assessed by funipuncture in pregnancies complicated by rhesus isoimmunization., Methods: One hundred twelve consecutive funipunctures were performed on 33 rhesus-negative gravidas of 21-36 weeks' gestation (median 30). Doppler flow, corrected for angle, was measured on the fetal descending aorta with pulsed Doppler equipment immediately before funipuncture. Differences between observed peak velocities and the calculated gestational age-dependent upper confidence limits (delta peak velocities) were compared with corresponding differences between observed hematocrits and the calculated lower confidence limits (delta hematocrits), and a regression analysis on the above paired difference values was performed. In addition, the correlation coefficient between delta peak velocities and delta hematocrits was calculated for the first procedure per pregnancy only., Results: The mean peak aortic velocity of anemic fetuses was higher than that of unaffected fetuses (P < .001); delta peak aortic velocities correlated negatively with delta hematocrits (r = -0.66, P < .001). The correlation coefficient between delta peak aortic velocities and delta hematocrits for the first procedure peer pregnancy only was r = -0.72 (P < .001). Prediction of fetal anemia by Doppler using gestational age-dependent 95% confidence limits was possible with positive and negative predictive values of 73 and 66%, respectively., Conclusion: Peak aortic velocity, a noninvasive assessment of fetal anemia, may be used as an additional test for monitoring pregnancies complicated by rhesus isoimmunization. However, the limited predictive capacity hampers its clinical usefulness.

Objective: To investigate the effect of anemia on fetal venous, arterial, and intracardiac blood flows., Methods: Color flow Doppler was used to record flow-velocity waveforms from the atrioventricular valves, ductus venosus, right hepatic vein, inferior vena cava, middle cerebral artery, and descending thoracic aorta from 38 cases of red blood cell isoimmunized pregnancies. Immediately after the Doppler studies, funipuncture was performed and the fetal hemoglobin concentration was measured., Results: Blood flow velocities in the thoracic aorta, middle cerebral artery, and the ductus venosus were increased compared to reference ranges established previously; however, a significant association with the degree of anemia was found only for the velocity in the thoracic aorta. Pulsatility indices in arteries and veins and the ratio of early to late atrioventricular inflow velocities were not significantly different from normal., Conclusions: Fetal anemia is associated with a hyperdynamic circulation in both arterial and venous vessels. Even in severe anemia, there is no evidence of congestive heart failure. Venous and intracardiac Doppler studies do not provide a clinically useful contribution in the management of red blood cell isoimmunization.

Rhesus iso-immunization is associated with fatal pulmonary hypoplasia. We have examined the hypothesis that abnormalities of lung volume, as an index of lung growth, may also be found in survivors. At a median age of nine months, lung volume was assessed by measurement of functional residual capacity in 23 patients affected antenatally by rhesus iso-immunization. Seventeen of the patients had required at least one intrauterine transfusion. Five patients (group A) had an FRC < 24 ml/kg (median 21 ml/kg, range 19-22 ml/kg) and the other 18 (group B) an FRC > or = 24 ml/kg (median 27 ml/kg, range 24-36 ml/kg) (p < 0.01). The only significant difference between these two groups was the timing of the first foetal blood sampling and intrauterine transfusion, being a median of 22 weeks (range 20-23 weeks) in group A and 30 weeks (range 17-36 weeks) in group B (p < 0.01).

Pulsed-Doppler examinations of blood-flow velocities in the umbilical artery were carried out before and after 15 diagnostic cordocenteses and 34 fetal blood transfusions into the umbilical vein. There were decreases in the systolic/diastolic ratio (A/B) (p < 0.01), the pulsatility index (PI) (p < 0.05), and the resistance index (RI) (p < 0.01) after cordocentesis but not after fetal blood transfusion. There were no correlations between the initial hematocrit and the umbilical artery Doppler indices in the sample nor in the fetal blood sampling group. In the fetal blood transfusion group, on the other hand, there was a negative correlation between the initial hematocrit and A/B (r = -0.44; p < 0.01) and the RI (r = -0.35; p < 0.05). The umbilical artery Doppler flow-velocity indices did not predict the fetal hematocrit.

Pulsed Doppler blood-flow velocity waveforms in the umbilical arteries, as well as blood gases, hematocrit, and lactate concentration in umbilical venous blood, were examined in 21 patients undergoing 49 cordocentesis, 34 of which were followed by fetal blood transfusion into the umbilical vein. The aim of the study was to evaluate the correlations, if any, between the Doppler indices from the umbilical artery (pulsatility index, resistance index, systolic/diastolic ratio) and the blood gas values (pO2, pCO2, O2 content, pH) and lactate content in the umbilical vein. The only correlation confirmed in this study was in the subgroup of anemic fetuses undergoing fetal blood transfusion, where correlation existed between A/B and the initial O2 content (r = -0.41, p < 0.02). We conclude that, in Rhesus-isoimmunized pregnancies, in contrast to other pregnancies, a close correlation does not exist between the Doppler indices in the umbilical artery and the fetal blood gas values.

Objective: To compare fetal ductus venosus blood flow velocities in anemic fetuses and normal controls and to study the effect of intravascular transfusion on ductus venosus flow velocities., Methods: Fetal ductus venosus flow velocities were measured using pulsed Doppler ultrasound in 21 anemic fetuses immediately before and after intravascular transfusion and again the day after transfusion. The control group consisted of 21 normal fetuses matched for gestational age., Results: In the anemic fetuses, ductus venosus flow velocities were significantly higher than in controls. Transfusion initially resulted in even higher flow velocities. The following day, ductus venosus flow velocities decreased to values comparable to those in the control group. The ratio of peak to minimum velocity was higher in the anemic fetuses., Conclusion: Our finding of increased ductus venosus blood flow in anemic fetuses supports the theory that in fetal anemia, venous return and therefore cardiac preload is increased. High peak to minimum velocity ratio may reflect increased atrial pressure as a sign of imminent congestive heart failure. Because blood passing through the ductus venosus is directed into the left atrium, increased ductus venosus blood flow in the anemic fetus may be an essential compensatory mechanism to maintain oxygen supply to vital organs such as the heart and brain.

A total of 164 hemoperfusions were administered to 60 pregnant patients with Rh sensitization and a history of perinatal death of the newborns from hemolytic disease. Hemoperfusion was found to decelerate the progress of hemolytic disease of the newborns promoting delivery of babies with more benign forms of the disease. The method efficacy was 76%. Dynamic follow-up of fetal functional status over the course of hemosorption treatment by examinations of biophysical profiles and ultrasonic dopplerometry has shown no negative effects of this treatment modality on fetal status.

Objective: To investigate the relation between umbilical vein blood gas components and the vascular resistance in four fetal arteries in Rh-immunised pregnancies., Design: A prospective observational study over a 4-month period., Setting: King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia., Subjects: Fifteen Rh-isoimmunised pregnant women., Interventions: Pulsed Doppler examinations of the umbilical artery, fetal internal carotid artery, thoracic aorta and abdominal aorta before transabdominal fetal blood sampling from the umbilical vein on 38 occasions., Main Outcome Measures: Doppler flow velocity pulsatility index (PI), systolic/diastolic ratio (A/B) and resistance index (RI) in the four fetal arteries investigated were related to the umbilical vein blood gases and acid-base status (PO2, PCO2, O2-content, CO2-content, HCO3, base excess and lactate concentration)., Results: There were no correlations between the Doppler indices in any of the vessels studied and the blood gases components in the umbilical vein. The ratios between the corresponding Doppler indices in the different vessels were also independent of the blood gases and acid-base status and there were no significant differences in the Doppler indices in the same vessel between fetuses with blood gas values over the 75th centile and those with values below the 25th centile., Conclusion: This study does not support a reduction in peripheral vascular resistance in the fetal cerebrum in relation to fetal hypoxia in Rh-immunized pregnancies.

Objective: We examined whether abnormal elevations in umbilical venous pressure during intravascular transfusion predict post-transfusion mortality., Methods: Umbilical venous pressures were measured during intravascular transfusion of human fetuses with Rhesus incompatibility. Five fetuses died within 24 hours after transfusion and nine fetuses survived the procedure., Results: Survivors and non-survivors were similar in demographic and clinical data, as well as in transfusion characteristics. The only difference between the groups was the change in umbilical venous pressure during the transfusion: 5.0 +/- 6.3 mmHg for survivors versus 18.1 +/- 10.4 mmHg for non-survivors (P = .01). An increase in the umbilical venous pressure of 10 mmHg or more predicted fetal death with a sensitivity of 80% and specificity of 89%., Conclusion: Based on these results, we have modified our transfusion technique. If the change in umbilical venous pressure during intravascular transfusion approaches 10 mmHg, we discontinue the procedure. If the change in pressure exceeds 10 mmHg during transfusion, we remove blood and replace it with an equal volume of saline.

Two cases of rhesus isoimmunization are presented in which the fetus was much more severely affected than anticipated and where a sinusoidal pattern found on cardiotocography, performed because of absent fetal movements, resulted in appropriate and successful management.

Objective: To study the relation between changes in the fetal thyroid hormone and thyroid stimulating hormone (TSH) concentrations and alterations in the fetal circulation as assessed by Doppler ultrasound., Design: A cross-sectional study of small for gestational age (SGA) and red-cell isoimmunized fetuses undergoing cordocentesis and Doppler studies for the assessment and determination of fetal karyotype, acid-base balance and haemoglobin concentration., Setting: Harris Birthright Research Centre for Fetal Medicine, King's College, London., Subjects: 38 growth retarded and 38 red-cell isoimmunised fetuses., Interventions: Cordocentesis., Main Outcome Measures: Serum TSH total and free thyroxine (T4, FT4) and total and free triiodothyronine (T3, FT3) concentrations; middle cerebral artery (MCAVm) and descending thoracic aorta (AoVm) mean blood velocities; fetal Po2 and haemoglobin concentration (Hb)., Results: Delta values (delta) calculated as the number of SDs from the respective normal mean for gestation were used to compare the results with those from a previous study of normal fetuses. Mean AoVm was increased in the isoimmunized fetuses (P less than 0.001) but decreased in the SGA fetuses (P less than 0.001). Mean MCAVm was increased in both groups (P less than 0.01; P less than 0.001). There were significant associations between the gestational age adjusted values for TSH and MCAVm (r = 0.23, P less than 0.05) and between T4, FT4 or FT3 and AoVm (r = 0.41, P less than 0.01; r = 0.50, P less than 0.01; r = 0.36, P less than 0.01 respectively). In addition, T4 and FT4 were associated with delta Po2 and delta Hb., Conclusion: In the hypoxaemic hypoxia of growth retardation and the anaemic hypoxia of rhesus disease there are significant associations between changes in fetal thyroid hormone concentrations and changes in fetal blood flow as assessed by Doppler. Irrespective of whether altered blood flow is the cause or effect of changes in thyroid hormone concentrations, the observed changes could have beneficial effects for fetal survival, in the presence of a hostile intrauterine environment.

The liver enzymes, aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP), were measured in the blood of 25 fetuses with severe Rh alloimmunization at the time of their first, second and third intravascular transfusions and in 17 comparison fetuses. In the comparison group, GGT increased with advancing gestation (r = 0.7; P = 0.002), whereas ALP, AST and ALT did not correlate with gestational age. Rh hydropic fetuses (n = 8) had higher blood ALT levels than the comparison fetuses (P = 0.008) had significantly increased transaminases when compared with non hydropic fetuses (n = 17). In hydropic fetuses, AST correlated with the nucleated red cell count before transfusion (r = 0.94; P = less than 0.0001). Fetal transaminases were no longer increased in hydropic fetuses by the second (AST) or third (ALT) transfusion. In both hydropic and non hydropic fetuses, GGT increased by the second transfusion (median percentage change +85%, range -83% to +596%; P = 0.003). The rise in fetal GGT was transitory and correlated with the increase in fetal haematocrit at the first transfusion (r = 0.58; P = 0.006). This study reports liver dysfunction secondary to extramedullary erythropoiesis in Rh alloimmunization and implicates portal hypertension for the rise in fetal GGT with transfusion.

In 68 red blood cell isoimmunized pregnancies the mean velocity of blood in the fetal aorta was measured by pulsed Doppler ultrasonography, and the fetal hemoglobin concentration was determined in blood samples obtained by cordocentesis. The values were compared to reference ranges of mean aortic velocity and hemoglobin for gestation, which were determined from 218 218 pregnancies that were not complicated by fetal hemolysis. In the red blood cell isoimmunized pregnancies there was a significant positive correlation between the aortic mean velocity and the hemoglobin deficit for the nonhydropic fetuses and a significant negative correlation between these two parameters for the hydropic fetuses.

Direct intravascular fetal transfusion under ultrasound guidance has become an important method of treating fetal anemia secondary to maternal red cell alloimmunization. An estimate of normal circulating volume would be useful in selecting the volume of donor blood to be transfused to achieve a desired final hematocrit. Thirty-five fetuses between 21 and 35 weeks of gestation underwent 67 direct intravascular transfusions. The fetoplacental volume relative to fetal weight estimated by ultrasound was found to be relatively constant throughout gestation at approximately 100 cm3/kg. The severity of fetal hemolytic disease and its treatment with intrauterine transfusions did not appear to alter the fetoplacental volume. A nomogram for fetoplacental blood volume versus gestational age is described.

Thirty-two patients with Rh-immunized pregnancies had amniocenteses between 16 and 20 weeks' gestation. Serial amniotic fluid values of delta optical density at 450 nm were studied to predict the severity of Rh disease. A value greater than 0.15 indicated severe Rh immunization. Values less than 0.09 indicated mild or no Rh disease; delta optical density at 450 nm between 0.09 and 0.15 require further evaluation to determine the trend. Midtrimester amniocentesis is a simple technique that helps to determine which patients may or may not require fetal blood sampling.

Doppler blood cell velocities were measured in the aortas, inferior vena cavas, and umbilical veins of fetuses from isoimmunized pregnancies and related to the hematocrit levels of the fetal blood determined at fetoscopy. Pourcelot Index of flow in the umbilical artery was similarly studied. The mean velocities in the descending aortas and the Pourcelot Indexes of the umbilical arteries of both normal and affected fetuses correlated with fetal age. These velocities and indexes of affected fetuses also correlated inversely with the fetal hematocrit levels independently of the correlation with fetal age. The affected fetuses had higher mean velocities in the aorta and in the inferior vena cava than did normal fetuses. A simple model of multiple regression predicted the fetal hematocrit levels with a mean error of 3.8 hematocrit units (volume %).